The invention pertains to novel N-acyl cycloalkylmethylamine derivatives having drug and bio-affecting properties and to their preparation, pharmaceutical formulations containing them and methods of use. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (i; N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. In mammals, melatonin levels show a cyclical, circadian pattern, with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology. ##STR1##
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [.sup.125 I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures.
Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific [.sup.125 I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting the melatonin receptors are located within the human biological dock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487.
Melatonin binding sites have been found in several diverse tissues of the body--i.e., in the retina, superchiasmatic nucleus, spleen, etc. Thus, melatonin exerts multiple physiological effects, is not highly selective, and its potential for producing side effects is significant. Melatonin agonists should be more selective than melatonin and give fewer side effects.
In addition, melatonin's metabolic profile can be problematic in that the compound degrades rapidly in vivo and its oral bioavailability is often low and variable. Suitable melatonin agonists could overcome these drawbacks, resulting in products having more predictability activity.
Thus, melatonin agonists should be particularly useful for the treatment of sleep disorders and other chronobiological disorders. Melatonin agonists would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, immune disorders, neuroendorine disorders, and a variety of sleep disorders.
Aside from simple indole derivatives of melatonin itself, various amide structures have been prepared and their use as melatonin ligands disclosed. In general these amide structures can be represented as: ##STR2## wherein Z is an aryl or heteroaryl system attached by a two carbon chain to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application EPA 527 687A disclose as melatonin ligands arylethylamines 1, ##STR3## wherein Ar' is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R.sub.1 is, inter alia, an alkyl or cycloalkyl group; and R.sub.2 is hydrogen or lower alkyl.
Horn and Dubocovich in European Patent Application EPA 420 064A disclose 2-amidotetralins 2 as melatonin ligands, ##STR4## wherein R.sub.1 is, inter alia, hydrogen, lower alkyl, or lower alkoxyl; R.sub.2 is, inter alia, hydrogen, halogen, or lower alkoxyl; R.sub.3 is, inter alia, hydrogen, or lower alkyl; R.sub.4 is, inter alia, lower alkyl, haloalkyl or cycloalkyl; and R.sub.5 is hydrogen, hydroxyl, halogen, oxo, aryl, lower alkyl or alkylaryl.
Langlois, et al., in Australian Patent Application AU-A-48729/93 disclose arylalkyl(thio)amides 3 as melatonergic ligands, ##STR5## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen, halogen, or lower alkyl; R.sub.3 and R.sub.4 are identical or different groups including, inter alia, hydrogen, halogen, or lower alkyl; R.sub.5 is hydrogen or lower alkyl; X is sulfur or oxygen and R.sub.7 is, inter alia, lower alkyl or alkenyl.
Bounnaud, et al. in FR 2640970 disclose 1-aryl-2-aminomethylcyclopropane carboxamides of type 4 as antidepressants and anxiolytics, ##STR6## wherein R.sub.1 and R.sub.2 are lower alkyl; R.sub.3 is hydrogen, alkyl, aralkyl or heteroaralkyl; R.sub.4, R.sub.5, and R.sub.6 are independently hydrogen or alkyl.
However these disclosures do not teach or suggest the novel melatonergic compounds of the present invention.